title: Absence of CD14 delays progression of prion diseases accompanied by increased microglial activation.
abstract: Prion diseases are fatal neurodegenerative disorders characterized by accumulation of PrP(Sc), vacuolation of neurons and neuropil, astrocytosis, and microglial activation. Upregulation of gene expressions of innate immunity-related factors, including complement factors and CD14, is observed in the brains of mice infected with prions even in the early stage of infections. When CD14 knockout (CD14(-/-)) mice were infected intracerebrally with the Chandler and Obihiro prion strains, the mice survived longer than wild-type (WT) mice, suggesting that CD14 influences the progression of the prion disease. Immunofluorescence staining that can distinguish normal prion protein from the disease-specific form of prion protein (PrP(Sc)) revealed that deposition of PrP(Sc) was delayed in CD14(-/-) mice compared with WT mice by the middle stage of the infection. Immunohistochemical staining with Iba1, a marker for activated microglia, showed an increased microglial activation in prion-infected CD14(-/-) mice compared to WT mice. Interestingly, accompanied by the increased microglial activation, anti-inflammatory cytokines interleukin-10 (IL-10) and transforming growth factor β (TGF-β) appeared to be expressed earlier in prion-infected CD14(-/-) mice. In contrast, IL-1β expression appeared to be reduced in the CD14(-/-) mice in the early stage of infection. Double immunofluorescence staining demonstrated that CD11b- and Iba1-positive microglia mainly produced the anti-inflammatory cytokines, suggesting anti-inflammatory status of microglia in the CD14(-/-) mice in the early stage of infection. These results imply that CD14 plays a role in the disease progression by suppressing anti-inflammatory responses in the brain in the early stage of infection.
authors.affiliation: Laboratory of Veterinary Hygiene, Graduate School of Veterinary Medicine, Hokkaido University, Kita-ku, Sapporo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Sakai
authors.forename: Rie
authors.initials: R
authors.lastname: Hasebe
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Chang-Hyun
authors.initials: CH
authors.lastname: Song
authors.forename: Akio
authors.initials: A
authors.lastname: Suzuki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Motohiro
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D053583:Interleukin-1beta; D018950:Lipopolysaccharide Receptors; D018620:PrPSc Proteins; D016753:Interleukin-10